Summary | Insights from the first trials in epigenetics in human: What is the way forward?

August 26, 2017 - Prof. Stephen Nicholls (Adelaide, Australia)

Professor Nicholls shared some of the insights from the first human trials on epigenetic approaches to treat CVD. The need for additional therapeutic strategies above and beyond statin therapy stems from the residual CV event risk that is observed in high risk patients despite effective statin treatment.

Treatment with apabetalone is the first epigenetic approach to treat CVD. The agent was first thought to increase synthesis of ApoA-I in the liver, which appears to associate with an increase in HDL, but also with increased cholesterol influx capacity. A range of molecular studies later also showed that apabetalone beneficially affected several other pathways that have a role in driving the atherosclerotic disease process. Examples include inflammation, complement system, a range of metabolic effects, vascular calcification and coagulation. Thus, apabetalone appears to favorably modify atherogenesis across the whole continuum from early formation of plaque to ultimate rupture of plaque and coagulation causing acute MI.

To date, clinical experience with apabetalone has been obtained in 706 participants of completed trials. Of those, 576 patients had either CAD or dyslipidemia. All patients were well treated according to standard of care. Initial clinical studies with apabetalone were in high risk CAD patients. Three phase II studies have been completed in CAD patients: ASSERT (12 weeks, n=299) examined lipid effects of apabetalone, as did SUSTAIN (24 weeks, n=176), and ASSURE (26 weeks, n=323) evaluated the effects of apabetalone on coronary atherosclerosis using IVUS. The phase III CV outcome trial BETonMACE is currently recruiting.

Upon treatment with apabetalone, an increase of plaque fibrous tissue was seen, a reduction in fibro-fatty tissue and an increase in plaque calcification; all aspects that suggest stabilization of plaque.

The early experience with increasing doses of apabetalone in patients with CAD treated with a statin, showed a significant, albeit modest dose-dependent increase in ApoA-1 and HDL-c. Importantly, robust increases were seen in large HDL-c particles, suggesting that the increased cholesterol efflux capacity observed in preclinical studies, can be translated to statin-treated CAD patients.28 Moreover, in ASSURE these modest changes translated into a trend towards regression of atheroma volume; changes in atheroma volume were as predicted based on the observed metabolic changes. The ASSURE study also looked into the effect of apabetalone on plaque composition with virtual histology. Upon treatment with apabetalone, an increase of plaque fibrous tissue was seen, a reduction in fibro-fatty tissue and an increase in plaque calcification; all aspects that suggest stabilization of plaque.29

Small imaging studies suggest that apabetalone may favorably impact both the size and the composition of plaque.

A later study examined attenuated plaque, which probably reflects a more vulnerable type of plaque, most likely containing more lipid and inflammation. Individuals with and without attenuated plaque do not differ much in respect to clinical features. At ESC 2017, it was presented that patients with attenuated plaque do show higher plaque burden as compared with those without attenuated plaque (atheroma volume: 43.8% vs. 37.5%, P=0.007 and total atheroma volume: 245.0 mm3 vs 193.6 mm3, P=0.005). This suggests that those more vulnerable lesions are also the more bulky lesions. The presented data suggest that apabetalone can reduce features of attenuated plaque on serial observations. Based on this small group of patients, these imaging studies suggest that apabetalone may favorably impact both the size and the composition of the plaque.

Biomarker analyses were also done in these phase II studies. A complementary story unfolds on biomarker effects, that is similar to some of the molecular biology results seen in preclinical studies. For instance, apabetalone reduces alkaline phosphatase activity in a dose-dependent manner in a clinical trial setting, which is thought to be an important parameter of plaque calcification. Moreover, apabetalone was found to reduce levels of osteoprotegerin, another factor important in regulating plaque calcification. Thus, the observed in vitro effects of apabetalone are also seen when humans were treated with it. In various cell models, expression of a range of factors involved in calcification was reduced upon apabetalone treatment. For instance in macrophages, apabetalone appears to have the capacity to reduce the inflammation-driven form of calcification, which occurs early in the atherosclerotic process. This implies that apabetalone has the potential to favorably impact the natural history of plaque, and ultimately CV events.

A downregulation of pathways involved in vascular calcification has also been observed in patients with chronic kidney disease (in a phase I safety and pharmacokinetic study). A single dose administration (100 mg) of apabetalone resulted in downregulation of vascular calcification mediators after 12 hours in these patients.

It is also known that apabetalone has favorable effects on vascular inflammation, and it inhibits atherosclerotic disease. In animal models, a reduction is seen in the expression of a range of inflammatory factors that are associated with the formation, progression and ultimately the rupture of atherosclerotic disease. Again, in the clinical studies apabetalone reduced a number of inflammatory markers, implying that the findings can be translated from bench to bedside.

Data from these early studies have been pooled, in order to look at early signals regarding CV events. The treatment groups differed slightly, with patients in the apabetalone group more likely to be male, older and to have more evidence of dyslipidemia. The percent changes in biochemical parameters were very similar to that seen in the individual studies. Apabetalone was superior as compared with placebo in terms of raising ApoA-I (6.7% vs. 2.7%, P<0.001) and HDL-c (6.5% vs. 0%, P<0.001), as well as the number of total HDL particles (4.8% vs 0.5%, P<0.001) and large HDL particles (23.3% s 1.7%, P<0.001). In addition, hsCRP was significantly more reduced with apabetalone (-21.1% vs -13.3%, P=0.04), consistent with the reduction in systemic inflammation in apabetalone-treated high-risk patients.

When looking at CV events in pooled data from phase II trials, a lower event rate was seen with apabetalone as compared with the placebo group (44% relative risk reduction, P=0.0232). Patients with DM showed a greater risk reduction (RRR: 57%, P=0.0151). Moreover, patients with an elevated CRP level at baseline also show a greater risk reduction (RRR: 62%, P=0.0166). These data give insight into which patients are more likely to have modifiable risk when treated with this drug. These small, short-term studies were not designed examine these issues, but they give some hope that CV benefits are seen when apabetalone treatment is studied in a larger trial.

Thus far, studies to date showed that apabetalone was well tolerated; across the three studies the most common adverse effects were similar to placebo, and consisted of gastrointestinal disorders and infections. With few exceptions, the adverse events were mild and moderate in severity. The most clinically significant adverse effect was a raise in hepatic ALT/AST levels. The effect of apabetalone on liver transaminases has been studied in detail in the phase II study. The incidence of transaminase elevation >3x ULN is quite stable at 7-8%. No cases of Hy’s law or serious hepatic injury have been reported in over 1000 subjects. Thus, although the transaminase levels increase, no clinical syndrome of liver injury was observed. Moreover, the transaminase elevations resolve rapidly following cessation of the drug. Both early and long-term hepatic safety will be further delineated in longer and larger studies, for instance in the CV outcomes trial that is currently enrolling patients. The BETonMACE evaluates treatment (up to 104 weeks) with apabetalone 200 mg or placebo in addition to standard of care in 2400 subjects at high risk following ACS, after a run-in period of 1-2 weeks with atorvastatin or rosuvastatin. It is an event-based trial that will continue until 250 events have occurred. All patients have T2DM and had a CAD event between 7 and 90 days prior to visit 1, and HDL-c should be <1.04 for males and <1.17 for females. These criteria are based on prior observations, focusing on the population with the possible greatest benefit with this therapy. The primary endpoint will be CV death, non-fatal MI and stroke, and a range of other clinical and biochemical effects will also be assessed throughout the course of the study.